scholarly journals Mitochondrial fission and fusion

2010 ◽  
Vol 47 ◽  
pp. 85-98 ◽  
Author(s):  
Iain Scott ◽  
Richard J. Youle
Keyword(s):  
Mitochondrial Fission ◽  
Adaptor Proteins ◽  
Cell Types ◽  
Mitochondrial Morphology ◽  
Mitochondrial Membranes ◽  
Mechanical Proteins ◽  
A Cell ◽  
Active Processes ◽  
Organelle Morphology ◽  
Cellular Organelles

Mitochondria are highly dynamic cellular organelles, with the ability to change size, shape and position over the course of a few seconds. Many of these changes are related to the ability of mitochondria to undergo the highly co-ordinated processes of fission (division of a single organelle into two or more independent structures) or fusion (the opposing reaction). These actions occur simultaneously and continuously in many cell types, and the balance between them regulates the overall morphology of mitochondria within any given cell. Fission and fusion are active processes which require many specialized proteins, including mechanical enzymes that physically alter mitochondrial membranes, and adaptor proteins that regulate the interaction of these mechanical proteins with organelles. Although not fully understood, alterations in mitochondrial morphology appear to be involved in several activities that are crucial to the health of cells. In the present chapter we discuss the mechanisms behind mitochondrial fission and fusion, and discuss the implications of changes in organelle morphology during the life of a cell.

scholarly journals Bcl-xL increases mitochondrial fission, fusion, and biomass in neurons

2009 ◽  
Vol 184 (5) ◽  
pp. 707-719 ◽  
Author(s):  
Sarah B. Berman ◽  
Ying-bei Chen ◽  
Bing Qi ◽  
J. Michael McCaffery ◽  
Edmund B. Rucker ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Mitochondrial Fission ◽  
Cell Types ◽  
Synaptic Activity ◽  
Mitochondrial Morphology ◽  
Cultured Neurons ◽  
Neuronal Dysfunction ◽  
Neuronal Processes ◽  
Organelle Morphology

Mitochondrial fission and fusion are linked to synaptic activity in healthy neurons and are implicated in the regulation of apoptotic cell death in many cell types. We developed fluorescence microscopy and computational strategies to directly measure mitochondrial fission and fusion frequencies and their effects on mitochondrial morphology in cultured neurons. We found that the rate of fission exceeds the rate of fusion in healthy neuronal processes, and, therefore, the fission/fusion ratio alone is insufficient to explain mitochondrial morphology at steady state. This imbalance between fission and fusion is compensated by growth of mitochondrial organelles. Bcl-xL increases the rates of both fusion and fission, but more important for explaining the longer organelle morphology induced by Bcl-xL is its ability to increase mitochondrial biomass. Deficits in these Bcl-xL–dependent mechanisms may be critical in neuronal dysfunction during the earliest phases of neurodegeneration, long before commitment to cell death.

The role of Drp1 adaptor proteins MiD49 and MiD51 in mitochondrial fission: implications for human disease

2016 ◽  
Vol 130 (21) ◽  
pp. 1861-1874 ◽  
Author(s):  
Kathleen Atkins ◽  
Asish Dasgupta ◽  
Kuang-Hueih Chen ◽  
Jeff Mewburn ◽  
Stephen L. Archer
Keyword(s):  
Cell Proliferation ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Adaptor Proteins ◽  
Cell Types ◽  
Mitochondrial Morphology ◽  
Disease States

Mitochondrial morphology is governed by the balance of mitochondrial fusion, mediated by mitofusins and optic atrophy 1 (OPA1), and fission, mediated by dynamin-related protein 1 (Drp1). Disordered mitochondrial dynamics alters metabolism, proliferation, apoptosis and mitophagy, contributing to human diseases, including neurodegenerative syndromes, pulmonary arterial hypertension (PAH), cancer and ischemia/reperfusion injury. Post-translational regulation of Drp1 (by phosphorylation and SUMOylation) is an established means of modulating Drp1 activation and translocation to the outer mitochondrial membrane (OMM). This review focuses on Drp1 adaptor proteins that also regulate fission. The proteins include fission 1 (Fis1), mitochondrial fission factor (Mff) and mitochondrial dynamics proteins of 49 kDa and 51 kDa (MiD49, MiD51). Heterologous MiD overexpression sequesters inactive Drp1 on the OMM, promoting fusion; conversely, increased endogenous MiD creates focused Drp1 multimers that optimize OMM scission. The triggers that activate MiD-bound Drp1 in disease states are unknown; however, MiD51 has a unique capacity for ADP binding at its nucleotidyltransferase domain. Without ADP, MiD51 inhibits Drp1, whereas ADP promotes MiD51-mediated fission, suggesting a link between metabolism and fission. Confusion over whether MiDs mediate fusion (by sequestering inactive Drp1) or fission (by guiding Drp1 assembly) relates to a failure to consider cell types used and to distinguish endogenous compared with heterologous changes in expression. We speculate that endogenous MiDs serve as Drp1-binding partners that are dysregulated in disease states and may be important targets for inhibiting cell proliferation and ischemia/reperfusion injury. Moreover, it appears that the composition of the fission apparatus varies between disease states and amongst individuals. MiDs may be important targets for inhibiting cell proliferation and attenuating ischemia/reperfusion injury.

scholarly journals Molecular Machinery and Pathophysiology of Mitochondrial Dynamics

2021 ◽  
Vol 9 ◽  
Author(s):  
Yi-Han Chiu ◽  
Shu-Chuan Amy Lin ◽  
Chen-Hsin Kuo ◽  
Chia-Jung Li
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Biological Significance ◽  
Lipid Synthesis ◽  
Mitochondrial Morphology ◽  
Animal Cells ◽  
Main Site ◽  
Mechanical Proteins ◽  
Molecular Machinery ◽  
Active Processes

Mitochondria are double-membraned organelles that exhibit fluidity. They are the main site of cellular aerobic respiration, providing energy for cell proliferation, migration, and survival; hence, they are called “powerhouses.” Mitochondria play an important role in biological processes such as cell death, cell senescence, autophagy, lipid synthesis, calcium homeostasis, and iron balance. Fission and fusion are active processes that require many specialized proteins, including mechanical enzymes that physically alter mitochondrial membranes, and interface proteins that regulate the interaction of these mechanical proteins with organelles. This review discusses the molecular mechanisms of mitochondrial fusion, fission, and physiopathology, emphasizing the biological significance of mitochondrial morphology and dynamics. In particular, the regulatory mechanisms of mitochondria-related genes and proteins in animal cells are discussed, as well as research trends in mitochondrial dynamics, providing a theoretical reference for future mitochondrial research.

scholarly journals Changes in the Expression of Mitochondrial Morphology-Related Genes during the Differentiation of Murine Embryonic Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Jeong Eon Lee ◽  
Bong Jong Seo ◽  
Min Ji Han ◽  
Yean Ju Hong ◽  
Kwonho Hong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Mitochondrial Fission ◽  
Expression Patterns ◽  
Embryonic Stem ◽  
Cell Types ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Stems Cells

During embryonic development, cells undergo changes in gene expression, signaling pathway activation/inactivation, metabolism, and intracellular organelle structures, which are mediated by mitochondria. Mitochondria continuously switch their morphology between elongated tubular and fragmented globular via mitochondrial fusion and fission. Mitochondrial fusion is mediated by proteins encoded by Mfn1, Mfn2, and Opa1, whereas mitochondrial fission is mediated by proteins encoded by Fis1 and Dnm1L. Here, we investigated the expression patterns of mitochondria-related genes during the differentiation of mouse embryonic stem cells (ESCs). Pluripotent ESCs maintain stemness in the presence of leukemia inhibitory factor (LIF) via the JAK-STAT3 pathway but lose pluripotency and differentiate in response to the withdrawal of LIF. We analyzed the expression levels of mitochondrial fusion- and fission-related genes during the differentiation of ESCs. We hypothesized that mitochondrial fusion genes would be overexpressed while the fission genes would be downregulated during the differentiation of ESCs. Though the mitochondria exhibited an elongated morphology in ESCs differentiating in response to LIF withdrawal, only the expression of Mfn2 was increased and that of Dnm1L was decreased as expected, the other exceptions being Mfn1, Opa1, and Fis1. Next, by comparing gene expression and mitochondrial morphology, we proposed an index that could precisely represent mitochondrial changes during the differentiation of pluripotent stem cells by analyzing the expression ratios of three fusion- and two fission-related genes. Surprisingly, increased Mfn2/Dnm1L ratio was correlated with elongation of mitochondria during the differentiation of ESCs. Moreover, application of this index to other specialized cell types revealed that neural stems cells (NSCs) and mouse embryonic fibroblasts (MEFs) showed increased Mfn2/Dnm1L ratio compared to ESCs. Thus, we suggest that the Mfn2/Dnm1L ratio could reflect changes in mitochondrial morphology according to the extent of differentiation.

scholarly journals Distinct molecular signatures of fission predict mitochondrial degradation or proliferation

2020 ◽  
Author(s):  
Tatjana Kleele ◽  
Timo Rey ◽  
Julius Winter ◽  
Sofia Zaganelli ◽  
Dora Mahecic ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Adaptor Proteins ◽  
Cellular Level ◽  
Mitochondrial Activity ◽  
Mitochondrial Morphology ◽  
Structured Illumination ◽  
Structured Illumination Microscopy ◽  
Downstream Effects ◽  
Fate Determinants

SUMMARYMitochondrial fission is a highly regulated process which, when disrupted, can alter metabolism, proliferation and apoptosis1–3. The downstream effects have implications for many diseases, from neurodegeneration4–6 to cardiovascular disease7,8 and cancer9,10. Key components of the fission machinery have been identified: constriction sites are initiated by the endoplasmic reticulum (ER)11 and actin12 before dynamin-related protein 1 (Drp1)13 is recruited to the outer mitochondrial membrane via adaptor proteins14–17, where it drives constriction and scission of the membrane18. In the life cycle of mitochondria, fission is important for the biogenesis of new mitochondria as well as the clearance of dysfunctional mitochondria via mitophagy3,19. Global regulation of fission on the cellular level is insufficient to explain how fate decisions are made at the single organelle level, so it is unknown how those dual functions arise, blocking progress in developing therapies that target mitochondrial activity. However, systematically studying mitochondrial division to uncover fate determinants is challenging, since fission is unpredictable, and mitochondrial morphology is extremely heterogeneous. Furthermore, because their ultrastructure lies below the diffraction limit, the dynamic organization of mitochondria and their interaction partners are hard to study at the single organelle level. We used live-cell structured illumination microscopy (SIM) and instant SIM20 for fast multi-colour acquisition of mitochondrial dynamics in Cos-7 cells and mouse cardiomyocytes. We analysed hundreds of fission events, and discovered two functionally and mechanistically distinct types of fission. Mitochondria divide peripherally to shed damaged material into smaller daughter mitochondria that subsequently undergo mitophagy, whereas healthy mitochondria proliferate via midzone division. Both types are Drp1-mediated, but they rely on different membrane adaptors to recruit Drp1, and ER and actin mediated pre-constriction is only involved in midzone fission.

scholarly journals CaM kinase Iα–induced phosphorylation of Drp1 regulates mitochondrial morphology

2008 ◽  
Vol 182 (3) ◽  
pp. 573-585 ◽  
Author(s):  
Xiao-Jian Han ◽  
Yun-Fei Lu ◽  
Shun-Ai Li ◽  
Taku Kaitsuka ◽  
Yasufumi Sato ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Time Lapse ◽  
Cell Types ◽  
Mitochondrial Morphology ◽  
Voltage Dependent ◽  
Dependent Protein ◽  
Time Lapse Imaging

Mitochondria are dynamic organelles that frequently move, divide, and fuse with one another to maintain their architecture and functions. However, the signaling mechanisms involved in these processes are still not well characterized. In this study, we analyze mitochondrial dynamics and morphology in neurons. Using time-lapse imaging, we find that Ca2+ influx through voltage-dependent Ca2+ channels (VDCCs) causes a rapid halt in mitochondrial movement and induces mitochondrial fission. VDCC-associated Ca2+ signaling stimulates phosphorylation of dynamin-related protein 1 (Drp1) at serine 600 via activation of Ca2+/calmodulin-dependent protein kinase Iα (CaMKIα). In neurons and HeLa cells, phosphorylation of Drp1 at serine 600 is associated with an increase in Drp1 translocation to mitochondria, whereas in vitro, phosphorylation of Drp1 results in an increase in its affinity for Fis1. CaMKIα is a widely expressed protein kinase, suggesting that Ca2+ is likely to be functionally important in the control of mitochondrial dynamics through regulation of Drp1 phosphorylation in neurons and other cell types.

scholarly journals Changes in the expression of mitochondrial morphology-related genes during the differentiation of murine embryonic stem cells

2019 ◽  
Author(s):  
Jeong Eon Lee ◽  
Bong Jong Seo ◽  
Min Ji Han ◽  
Yean Ju Hong ◽  
Kwonho Hong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Mitochondrial Fission ◽  
Expression Patterns ◽  
Embryonic Stem ◽  
Cell Types ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Stems Cells

AbstractDuring embryonic development, cells undergo changes in gene expression, signaling pathway activation/inactivation, metabolism, and intracellular organelle structures, which are mediated by mitochondria. Mitochondria continuously switch their morphology between elongated tubular and fragmented globular via mitochondrial fusion and fission. Mitochondrial fusion is mediated by proteins encoded by Mfn1, Mfn2, and Opa1, whereas mitochondrial fission is mediated by proteins encoded by Fis1 and Dmn1L. Here, we investigated the expression patterns of mitochondria-related genes during the differentiation of mouse embryonic stem cells (ESCs) in response to leukemia inhibitory factor (LIF) withdrawal. The expression of Mfn2 and Dnm1L was, as expected, increased and decreased, respectively. By comparing gene expression and mitochondrial morphology, we proposed an index that could precisely represent mitochondrial changes during the differentiation of pluripotent stem cells by analyzing the expression ratios of three fusion- and two fission-related genes. Surprisingly, increased Mfn2/Dnm1L ratio was correlated with elongation of mitochondria during the differentiation of ESCs. Moreover, application of this index to other specialized cell types revealed that neural stems cells (NSCs) and mouse embryonic fibroblasts (MEFs) showed increased Mfn2/Dnm1L ratio compared to ESCs. Thus, we suggest that the Mfn2/Dnm1L ratio could reflect changes in mitochondrial morphology according to the extent of differentiation.

scholarly journals Posttranslational modifications of mitochondrial fission and fusion proteins in cardiac physiology and pathophysiology

2019 ◽  
Vol 316 (5) ◽  
pp. C583-C604 ◽  
Author(s):  
Stephanie M. Adaniya ◽  
Jin O-Uchi ◽  
Michael W. Cypress ◽  
Yoichiro Kusakari ◽  
Bong Sook Jhun
Keyword(s):  
Posttranslational Modifications ◽  
Fusion Proteins ◽  
Molecular Mechanisms ◽  
Mitochondrial Fission ◽  
Cell Types ◽  
Mitochondrial Morphology ◽  
Mitochondrial Fragmentation ◽  
Physiological Relevance ◽  
Future Potential ◽  
The Stability

Mitochondrial fragmentation frequently occurs in chronic pathological conditions as seen in various human diseases. In fact, abnormal mitochondrial morphology and mitochondrial dysfunction are hallmarks of heart failure (HF) in both human patients and HF animal models. A link between mitochondrial fragmentation and cardiac pathologies has been widely proposed, but the physiological relevance of mitochondrial fission and fusion in the heart is still unclear. Recent studies have increasingly shown that posttranslational modifications (PTMs) of fission and fusion proteins are capable of directly modulating the stability, localization, and/or activity of these proteins. These PTMs include phosphorylation, acetylation, ubiquitination, conjugation of small ubiquitin-like modifier proteins, O-linked- N-acetyl-glucosamine glycosylation, and proteolysis. Thus, understanding the PTMs of fission and fusion proteins may allow us to understand the complexities that determine the balance of mitochondrial fission and fusion as well as mitochondrial function in various cell types and organs including cardiomyocytes and the heart. In this review, we summarize present knowledge regarding the function and regulation of mitochondrial fission and fusion in cardiomyocytes, specifically focusing on the PTMs of each mitochondrial fission/fusion protein. We also discuss the molecular mechanisms underlying abnormal mitochondrial morphology in HF and their contributions to the development of cardiac diseases, highlighting the crucial roles of PTMs of mitochondrial fission and fusion proteins. Finally, we discuss the future potential of manipulating PTMs of fission and fusion proteins as a therapeutic strategy for preventing and/or treating HF.

Dendritic cells of the human epidermis: immuno-electron microscopic studies of la antigen reactivity

1978 ◽  
Vol 36 (2) ◽  
pp. 644-645
Author(s):  
G. Rowden ◽  
M. G. Lewis ◽  
T. M. Phillips
Keyword(s):  
Dendritic Cells ◽  
Langerhans Cells ◽  
Cell Types ◽  
Cell Type ◽  
Electron Microscopic ◽  
La Antigen ◽  
Microscopic Studies ◽  
A Cell ◽  
C3 Receptors ◽  
Antigen Reactivity

Langerhans cells of mammalian stratified squamous epithelial have proven to be an enigma since their discovery in 1868. These dendritic suprabasal cells have been considered as related to melanocytes either as effete cells, or as post divisional products. Although grafting experiments seemed to demonstrate the independence of the cell types, much confusion still exists. The presence in the epidermis of a cell type with morphological features seemingly shared by melanocytes and Langerhans cells has been especially troublesome. This so called "indeterminate", or " -dendritic cell" lacks both Langerhans cells granules and melanosomes, yet it is clearly not a keratinocyte. Suggestions have been made that it is related to either Langerhans cells or melanocyte. Recent studies have unequivocally demonstrated that Langerhans cells are independent cells with immune function. They display Fc and C3 receptors on their surface as well as la (immune region associated) antigens.

scholarly journals Mitochondrial fission and mitophagy are independent mechanisms regulating ischemia/reperfusion injury in primary neurons

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Anthony R. Anzell ◽  
Garrett M. Fogo ◽  
Zoya Gurm ◽  
Sarita Raghunayakula ◽  
Joseph M. Wider ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Conditional Knockout ◽  
Mitochondrial Morphology ◽  
Primary Neurons ◽  
Mitochondrial Fragmentation

AbstractMitochondrial dynamics and mitophagy are constitutive and complex systems that ensure a healthy mitochondrial network through the segregation and subsequent degradation of damaged mitochondria. Disruption of these systems can lead to mitochondrial dysfunction and has been established as a central mechanism of ischemia/reperfusion (I/R) injury. Emerging evidence suggests that mitochondrial dynamics and mitophagy are integrated systems; however, the role of this relationship in the context of I/R injury remains unclear. To investigate this concept, we utilized primary cortical neurons isolated from the novel dual-reporter mitochondrial quality control knockin mice (C57BL/6-Gt(ROSA)26Sortm1(CAG-mCherry/GFP)Ganl/J) with conditional knockout (KO) of Drp1 to investigate changes in mitochondrial dynamics and mitophagic flux during in vitro I/R injury. Mitochondrial dynamics was quantitatively measured in an unbiased manner using a machine learning mitochondrial morphology classification system, which consisted of four different classifications: network, unbranched, swollen, and punctate. Evaluation of mitochondrial morphology and mitophagic flux in primary neurons exposed to oxygen-glucose deprivation (OGD) and reoxygenation (OGD/R) revealed extensive mitochondrial fragmentation and swelling, together with a significant upregulation in mitophagic flux. Furthermore, the primary morphology of mitochondria undergoing mitophagy was classified as punctate. Colocalization using immunofluorescence as well as western blot analysis revealed that the PINK1/Parkin pathway of mitophagy was activated following OGD/R. Conditional KO of Drp1 prevented mitochondrial fragmentation and swelling following OGD/R but did not alter mitophagic flux. These data provide novel evidence that Drp1 plays a causal role in the progression of I/R injury, but mitophagy does not require Drp1-mediated mitochondrial fission.

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